Validation of Matrix Metalloproteinase-9 (MMP-9) as a Novel Target for Treatment of Diabetic Foot Ulcers in Humans and Discovery of a Potent and Selective Small-Molecule MMP-9 Inhibitor That Accelerates Healing

J Med Chem. 2018 Oct 11;61(19):8825-8837. doi: 10.1021/acs.jmedchem.8b01005. Epub 2018 Sep 27.

Abstract

Diabetic foot ulcers (DFUs) are a significant health problem. A single existing FDA-approved drug for this ailment, becaplermin, is not standard-of-care. We previously demonstrated that upregulation of active matrix metalloproteinase (MMP)-9 is the reason that the diabetic wound in mice is recalcitrant to healing and that MMP-8 participates in wound repair. In the present study, we validate the target MMP-9 by identifying and quantifying active MMP-8 and MMP-9 in human diabetic wounds using an affinity resin that binds exclusively to the active forms of MMPs coupled with proteomics. Furthermore, we synthesize and evaluate enantiomerically pure ( R)- and ( S)-ND-336, as inhibitors of the detrimental MMP-9, and show that the ( R)-enantiomer has superior efficacy in wound healing over becaplermin. Our results reveal that the mechanisms of pathology and repair are similar in diabetic mice and diabetic humans and that ( R)-ND-336 holds promise for the treatment of DFUs as a first-in-class therapeutic.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetic Foot / drug therapy*
  • Diabetic Foot / enzymology
  • Diabetic Foot / etiology
  • Drug Discovery*
  • Female
  • Humans
  • Matrix Metalloproteinase 9 / chemistry*
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors / chemistry
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Proteomics
  • Wound Healing / drug effects*

Substances

  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinase 9